This invention relates to novel hygromycin A derivatives that are useful as antibacterial and antiprotozoal agents in mammals, including man, as well as in fish and birds. This invention also relates to pharmaceutical compositions containing the novel compounds and to methods of treating bacterial and protozoal infections in mammals, fish and birds by administering the novel compounds to mammals, fish and birds requiring such treatment.
Hygromycin A is a fermentation-derived natural product first isolated from Streptomyces hygroscopicus in 1953. As an antibiotic, hygromycin A possesses activity against human pathogens and is reported to possess potent in vitro activity against Serpulina (Treponema) hyodysenteriae which causes swine dysentery. Several references refer to semisynthetic modifications of hygromycin A, including the following: derivatization of the 5" ketone of hygromycin A to the 2,4-dinitrophenylhydrazone is referred to in K. Isono et al., J. Antibiotics 1957, 10, 21, and R. L. Mann and D. O. Woolf, J. Amer Chem. Soc. 1957, 79, 120. K. Isono et al., ibid., also refer to the thiosemicarbazone at 5"; reduction of the 5" ketone of hygromycin A to the 5" alcohol is referred to in R. L. Mann and D. O. Woolf, ibid., as well as in S. J. Hecker et al., Bioorg. Med. Chem. Lett. 1992, 2, 533 and S. J. Hecker et al., Bioorg. Med. Chem. Lett. 1993, 3, 295; furanose analogues are referred to in B. H. Jaynes et al., Bioorg. Med. Chem. Lett. 1993, 3, 1531, and B. H. Jaynes et al., J. Antibiot. 1992, 45, 1705; aromatic ring analogues are referred to in S. J. Hecker et al., Bioorg. Med. Chem. Lett. 1993, 3, 289, and C. B. Cooper et al., Bioorg. Med. Chem. Lett. 1997, 7, 1747; enamide analogues are referred to in S. J. Hecker et al., Bioorg. Med. Chem. Lett. 1992, 2, 533; aminocyclitol analogues are referred to in S. J. Hecker et al., Bioorg. Med. Chem. Lett. 1992, 2, 1015, and in S. J. Hecker et al., Bioorg. Med. Chem. Lett. 1992, 2, 1043. The hygromycin A derivatives of the present invention possess broad activity against both gram-negative and gram-positive bacteria and protozoa. Hygromycin A derivatives are also described and claimed in U.S. provisional patent application Nos. 60/084,042 (filed May 4, 1998) and 60/084,058 (filed May 4, 1998), both of which U.S. provisional applications are incorporated herein by reference in their entirety.